Abstract
Microalbuminuria and hyperuricemia management are crucial for the integrated management of hypertensive patients. This retrospective post hoc analysis aims to evaluate the optimal allisartan‐isoproxil‐based combination regimen for hypertensive patients with microalbuminuria or hyperuricemia. A total of 460 hypertensive patients with microalbuminuria and 486 hypertensive patients with hyperuricemia were included in this study. All patients were initially treated with allisartan‐isoproxil for 4 weeks. Thereafter, patients with blood pressure (BP) < 140/90 mmHg continued the monotherapy for 8 weeks; patients with BP ≥140/90 mmHg were randomly assigned in a 1:1 ratio to receive allisartan‐isoproxil + amlodipine (Group A + C) or allisartan‐isoproxil + indapamide (Group A + D) for 8 weeks. The changes of BP, urinary albumin and serum uric acid (UA) were measured. In patients with microalbuminuria, the urinary albumin/creatinine ratio (UACR) significantly decreased by 10.4 mg/g in Group A + C (vs. baseline p = .0035) and 24.2 mg/g in Group A + D (vs baseline p < .0001), intergroup p = NS. In patients with hyperuricemia, serum UA level decreased by 44.5 µmol/L in Group A + C (vs. baseline p = .0003), but increased by 27.2 µmol/L in Group A + D (vs. baseline p = .0167), intergroup p < .0001. The results suggest that for hypertensive patients with microalbuminuria, angiotensin receptor blocker (ARB) + calcium channel blocker (CCB) or ARB+ diuretic both are good choices based on their improvement of microalbuminuria and BP. But for patients with hyperuricemia, ARB + diuretic may further increase the level of UA.
Keywords: allisartan‐isoproxil, combination regimen, hypertension, hyperuricemia, microalbuminuria
1. INTRODUCTION
The incidence of microalbuminuria or hyperuricemia in hypertensive patients is higher. Data showed that the detection rate of microalbuminuria in Chinese patients with essential hypertension is 28.8–42.9%, with urinary albumin excretion increasing along with BP rising. 1 , 2 Meanwhile, hypertension and hyperuricemia often coexist with the prevalence high up to 18.3–38.7% according to epidemiology data. 3 , 4
Hypertension can lead to the damage of target organs such as heart and kidney. Microalbuminuria is considered as a marker of early renal damage caused by hypertension, 5 , 6 and its persistence may increase the risk of cardiovascular events. 7 , 8 Microalbuminuria detection is a simple, sensitive and reliable test capable of early discovery of renal damage. Meanwhile, positive treatment of microalbuminuria can improve cardiovascular and renal prognosis of patients. 9
On the other hand, hyperuricemia has been given considerable attention as an independent risk factor for cardiovascular diseases as well. 10 , 11 The risk of microalbuminuria increased by 3.9% as serum UA level rising by every 10‐unit, suggesting that serum UA is associated with early kidney damage in hypertensive patients. 12 Thus, the importance of concurrent intervention in hypertension with hyperuricemia has been widely recognized during clinical practice in China. 13
Allisartan‐isoproxil is a selective nonpeptide ARB independently developed in China, which produces EXP‐3174 via gastrointestinal esterases metabolism, the same active metabolite of losartan potassium via hepatic metabolism, with microalbuminuria and UA metabolism improvement effects. 14 , 15 , 16 Therefore, this study aims to evaluate the effects of allisartan‐isoproxil‐based combination antihypertensive regimen through urinary albumin and serum uric acid (UA) levels in Chinese hypertensive patients.
2. METHODS
2.1. Study design
This is a retrospective post hoc analysis of treatment data for hypertensive patients with microalbuminuria or hyperuricemia from phase IV clinical trial of allisartan‐isoproxil. The phase IV study was approved by the Ethics Committee of Peking University People's Hospital (ethics no.: 2015 PHA043) and was conducted in accordance with the Declaration of Helsinki. All patients provided written informed consent before study enrollment. Patients who met the inclusion criteria (mentioned below) were selected as participants at 44 study sites (China FDA‐approved clinical pharmacology base hospitals) in China nationwide.
2.2. Inclusion criteria
Patients with essential hypertension who met the criteria of the Chinese Hypertension Guidelines, 17 aged 18−75 years, with body mass index (BMI) of 18.5–30 kg/m2, sitting systolic (SBP) and/or sitting diastolic BP (DBP) of 140/90∼ < 180/110 mmHg (1 mmHg = 0.133 kPa), and who signed the informed consent forms were eligible. Among them, patients with essential hypertension and microalbuminuria were determined based on the UACR of 30−300 mg/g. 18 And patients with essential hypertension and hyperuricemia also need to meet additional hyperuricemia criteria, which is defined as serum UA level ≥420 µmol/L in males and ≥360 µmol/L in females. 19 , 20
2.3. Exclusion criteria
Patients with known or suspected secondary hypertension, severe arrhythmia, and atrial fibrillation; patients with a history of acute coronary syndrome, heart failure, cerebrovascular diseases, or poorly controlled diabetes mellitus (fasting glucose > 11.0 mmol/L) within 6 months from the date of participant selection were excluded.
2.4. Study medications
Allisartan‐isoproxil tablets (240‐mg tablet), indapamide sustained‐release tablets (1.5‐mg tablet), amlodipine besylate tablets (5‐mg tablet), and allisartan‐isoproxil placebo 240‐mg tablet. Each drug was orally administered once daily in the morning. The drugs were all provided by Shenzhen Salubris Pharmaceuticals Co. Ltd.
2.5. Drug treatment process
After a 2‐week placebo washout period, the patients received 240 mg/day of allisartan‐isoproxil alone for 4 weeks. Patients with controlled BP (< 140/90 mmHg) continued the original treatment for 8 weeks. On the other hand, patients with uncontrolled BP (≥140/90 mmHg) were randomized, via a clinical trial remote electronic data capture system (EDC), in a ratio of 1: 1 into either allisartan‐isoproxil tablets (240 mg/day) + amlodipine besylate tablets (5 mg/day) group (Group A + C) or allisartan‐isoproxil tablets (240 mg/day) + indapamide sustained‐release tablets (1.5 mg/day) group (Group A + D). The patients received the respective combination therapy for 8 weeks. Baseline demographic data before monotherapy, including sitting BP, heart rate, sex, and biochemical parameters, such as the level of urinary albumin and serum UA, were recorded. Only the data of patients who were positive for microalbuminuria or hyperuricemia were analyzed in this study.
2.6. BP measurement method
The participants’ sitting BPs in the clinic were measured using Omron 1300 automatic BP measuring equipment. The participants were required to rest quietly for at least 5 min in a sitting position before the measurements, with their upper arms at the same level as their hearts during the measurements. Then, the measurements were repeated 2 min apart, averaging the three readings. For example, if there were differences of ≥ 10 mmHg in SBP and differences of ≥ 5 mmHg in DBP in any of the three readings, two additional measurements had to be performed, with the mean of the three measurements being used after removing the maximum and minimum measurements (the mean value had to be rounded to an integer).
2.7. Biochemical analyze
Morning blood and urine samples were collected after 8 h overnight fasting at week 0 and 12 at hospital for biochemical analyses. All tests were performed in accordance with the ethical requirements. Serum UA levels were tested via Beckman biochemistry analyzer. Urinary albumin concentration was measured by nephelometry, urinary creatinine levels were detected by an enzymatic method, and the ratio of the two indicators (urinary albumin /urinary creatinine) is UACR (mg/g). The intergroup and interassay coefficient of variation values were < 10%.
2.8. Evaluation endpoints
The primary endpoints were the difference in UACR of hypertensive patients with microalbuminuria between week 0 and 12 in group A+C and group A+D, and the difference in serum UA of hypertensive patients with hyperuricemia between week 0 and 12 in group A+C and group A+D.
The secondary endpoints were the rate of BP control (< 140/90 mmHg) at week 12, the decrease in mean sitting BP between week 0 and 12, the difference in UACR levels between week 0 and 12 in hypertensive patient with microalbuminuria who were administrated with monotherapy all the time, the difference in serum UA levels between week 0 and 12 in hypertensive patient with hyperuricemia who were administrated with monotherapy all the time.
2.9. Statistical methods
The two‐sided test was used for all statistical tests, with p<.05 considered statistically significant. The quantitative variables, such as the age of the patients in the two groups, were compared by using the Student's t‐test and Wilcoxon rank sum test, and categorical variables, such as sex of the two groups, were compared by using the Chi‐squared test/Fisher's exact test. A multivariate logistic regression analysis on influencing factors of the recovery of ACR and hyperuricemia was performed. All the statistical analyses were performed via SAS 9.4.
3. RESULTS
3.1. Patient screening
A total of 2126 patients with essential hypertension were enrolled in the clinical study, and 845 patients met the diagnosis criteria for hyperuricemia or microalbuminuria. Among them, 101 patients had both microalbuminuria and hyperuricemia, 359 patients had microalbuminuria alone, and 385 patients had hyperuricemia alone. As a whole, there is 21.6% (n = 460) of patients had hypertension with microalbuminuria, and 22.9% of patients enrolled (n = 486) had hypertension with hyperuricemia. See Figure 1.
FIGURE 1.
Flowchart of treatment of patients with hypertension and microalbuminuria or hyperuricemia. A + D, allisartan‐isoproxil tablets (240 mg) + indapamide sustained‐release tablets (1.5 mg); A + C, allisartan‐isoproxil tablets (240 mg) + amlodipine besylate tablets (5 mg).
3.2. Analysis of hypertensive patients with microalbuminuria
3.2.1. Baseline characteristics
A total of 460 patients had hypertension with microalbuminuria. There was no significant difference in baseline data between the two combined treatment groups, as shown in Table 1. Notably, the baseline BP levels of patients who always received monotherapy during 12‐week follow‐up period were lower than that of patients who transferred to combination therapy from week 5.
TABLE 1.
General characteristics of patients with hypertension and microalbuminuria at baseline.
| Combination therapies | ||||||
|---|---|---|---|---|---|---|
| Parameters | Total (No. = 460) | Group A (No. = 305) | Group A + C (No. = 81) | Group A + D (No. = 74) | Statistics | p a |
| Age (years) | 55.3 ± 10.01 | 55.3 ± 10.19 | 54.6 ± 9.86 | 55.9 ± 9.47 | 0.6731 | .4132 |
| BMI (kg/m2) | 25.8 ± 2.58 | 25.6 ± 2.60 | 26.1 ± 2.50 | 26.3 ± 2.51 | 0.1169 | .7328 |
| SBP (mmHg) | 151.2 ± 10.50 | 148.8 ± 9.74 | 155.2 ± 10.45 | 157.0 ± 10.11 | 1.1363 | .2881 |
| DBP (mmHg) | 92.4 ± 8.78 | 91.2 ± 8.11 | 95.5 ± 9.88 | 93.7 ± 9.28 | 1.4474 | .2308 |
| HR (bpm) | 74.2 ± 9.26 | 74.2 ± 9.22 | 73.0 ± 8.42 | 75.6 ± 10.18 | 3.1259 | .0790 |
| Fasting glucose (mmol/L) | 6.0 ± 1.30 | 5.9 ± 1.32 | 6.0 ± 1.26 | 6.0 ± 1.30 | 0.0583 | .8095 |
| TC (mmol/L) | 5.1 ± 1.16 | 5.0 ± 1.03 | 5.1 ± 1.02 | 5.3 ± 1.70 | −0.0161 | .9871 |
| TG (mmol/L) | 2.0 ± 1.41 | 2.0 ± 1.37 | 1.9 ± 1.09 | 2.1 ± 1.82 | −0.4263 | .6699 |
| SCr (µmol/L) | 70.4 ± 17.22 | 69.2 ± 17.46 | 72.2 ± 15.32 | 73.5 ± 17.85 | 0.2253 | .6357 |
| UACR (mg/g) | 84.9 ± 58.77 | 87.8 ± 62.27 | 74.9 ± 43.01 | 83.7 ± 58.28 | 0.1970 | .8438 |
| eGFR (mL/min/1.73 m2) | 99.6 ± 52.55 | 101.3 ± 62.93 | 96.5 ± 18.71 | 96.2 ± 21.69 | 0.0070 | .9337 |
Abbreviations: BMI, body mass index; eGFR, estimated glomerular filtration rate; DBP, diastolic blood pressure; HR, heart rate; SBP, systolic blood pressure; SCr, serum creatinine; TC, total cholesterol; TG, triglycerides; UA, uric acid; UACR, urinary albumin/creatinine ratio.
aThe distributions of TC, TG, and UACR were skewed, and the Wilcoxon rank sum test was used for their inter‐group comparisons; for other measures, Student's t‐test was used.
3.2.2. Efficacy evaluation of overall and allisartan‐isoproxil monotherapy
After a 4‐weeks of treatment with allisartan‐isoproxil 240 mg/day, 66.3% (305/460) of patients’ BP was controlled (BP < 140/90 mmHg), and continued the monotherapy for the following 8 weeks. Ultimately, the decrease in sitting SBP/DBP was 19.5 ± 12.2/11.1 ± 9.1 mmHg (both p < .0001), and the decrease in UACR was 14.0 mg/g from the baseline (p < .0001).
3.2.3. Efficacy evaluation of combination therapies
At week 5, patients with uncontrolled BP were transferred to combination therapy. After a subsequent 8‐week treatment with A + C, the sitting SBP/DBP decreased by 21.0 ± 13.4/11.4 ± 8.7 mmHg, and UACR had decreased by 10.4 mg/g (p = .0035) from the baseline. After an 8‐week treatment with A + D, the sitting SBP/DBP decreased by 23.0 ± 12.2/10.1 ± 8.2 mmHg (both p < .0001), and UACR decreased by 24.2 mg/g (p < .0001) from the baseline. No statistically significant differences were observed between the two groups. See Table 2 and Figure 2.
TABLE 2.
Changes in BP and urinary albumin level before and after treatment in patients with hypertension and microalbuminuria at baseline.
| Group | Parameters | Pre‐treatment | Post‐treatment | Change (week 12‐ baseline) | Statistics | p |
|---|---|---|---|---|---|---|
| Group A + C (No. = 81) | SBP (mmHg) | 155.2 ± 10.45 | 134.3 ± 12.93 | −21.0 ± 13.38 | 13.68 | <.0001 |
| DBP (mmHg) | 95.5 ± 9.88 | 84.3 ± 9.18 | −11.4 ± 8.73 | 11.4325 | <.0001 | |
| UACR (mg/g) | 74.9 ± 43.01 | 66.2 ± 76.00 | −10.4 ± 64.61 | −532.5 | .0035 | |
| Group A + D (No. = 74) | SBP (mmHg) | 157.0 ± 10.11 | 134.4 ± 11.42 | −23.0 ± 12.23 | 15.415 | <.0001 |
| DBP (mmHg) | 93.7 ± 9.28 | 83.6 ± 7.12 | −10.1 ± 8.21 | 10.1049 | <.0001 | |
| UACR (mg/g) | 83.7 ± 58.28 | 59.1 ± 63.17 | −24.2 ± 48.88 | −722 | <.0001 |
The distributions of UACR were skewed, and the Wilcoxon rank sum test was used for their intra‐group comparisons; for other measures, the paired t‐test was used. Abbreviations: A + D, allisartan‐isoproxil tablets (240 mg) + indapamide sustained‐release tablets (1.5 mg); A + C, allisartan‐isoproxil tablets (240 mg) + amlodipine besylate tablets (5 mg); UACR, urinary albumin/creatinine ratio.
FIGURE 2.
The levels of albumin/creatinine ratio (UACR) in Group A + C and Group A + D at baseline and 12 week. A + D, allisartan‐isoproxil tablets (240 mg) + indapamide sustained‐release tablets (1.5 mg); A + C, allisartan‐isoproxil tablets (240 mg) + amlodipine besylate tablets (5 mg).
3.2.4. Logistic regression analysis on influencing factors of the recovery of UACR
The multivariate logistic regression model to describe the recovery of UACR (< 30 mg/g) was developed using antihypertensive regimen, sex, age, BMI, history of diabetes, concomitant disease/medications, BP decrease, and eGFR as the variables. The results showed that A + C regimen and A + D regimen has a similar influence on improving microalbuminuria [OR (95% CI) = 0.688(0.344, 1.376), p = .2902]. See Figure 3.
FIGURE 3.
Multivariate regression analysis of the recovery of UACR at week 12 in patients with hypertension and microalbuminuria. A + D, allisartan‐isoproxil tablets (240 mg) + indapamide sustained‐release tablets (1.5 mg); A + C, allisartan‐isoproxil tablets + amlodipine besylate tablets (5 mg); BMI, body mass index; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; SBP, systolic blood pressure.
3.3. Analysis of hypertensive patients with hyperuricemia
3.3.1. Baseline characteristics
The baseline information of hypertensive patients with hyperuricemia (n = 486) is shown in Table 3. There was no significant difference in baseline data between the two combination treatment groups. The baseline BP levels of patients who always received monotherapy during 12‐week follow‐up period were significantly lower than that of patients in two combination treatment groups.
TABLE 3.
General characteristics of patients with hypertension and hyperuricemia at baseline.
| Combination therapies | ||||||
|---|---|---|---|---|---|---|
| Parameters | Total (No. = 486) | Group A (No. = 326) | Group A + C (No. = 77) | Group A + D (No. = 83) | Statistics | p a |
| Age (years) | 52.8 ± 11.27 | 53.0 ± 11.18 | 51.2 ± 13.20 | 53.4 ± 9.56 | 1.5797 | .2107 |
| BMI (kg/m2) | 25.8 ± 2.60 | 25.6 ± 2.60 | 26.1 ± 2.57 | 26.3 ± 2.58 | 0.1652 | .6849 |
| SBP (mmHg) | 149.7 ± 10.28 | 147.9 ± 9.56 | 154.0 ± 10.41 | 152.6 ± 11.07 | 0.7240 | .3961 |
| DBP (mmHg) | 92.9 ± 8.26 | 91.4 ± 7.60 | 96.1 ± 9.25 | 95.4 ± 8.40 | 0.2574 | .6126 |
| HR (bpm) | 74.2 ± 9.42 | 73.4 ± 9.30 | 75.7 ± 9.11 | 75.6 ± 9.91 | 0.0025 | .9600 |
| Fasting glucose (mmol/L) | 5.8 ± 1.15 | 5.8 ± 1.12 | 5.9 ± 1.41 | 5.8 ± 0.98 | 0.7632 | .3836 |
| TC (mmol/L) | 5.1 ± 1.21 | 5.1 ± 1.06 | 5.1 ± 1.16 | 5.2 ± 1.71 | 0.0621 | .9505 |
| TG (mmol/L) | 2.3 ± 1.63 | 2.3 ± 1.67 | 2.5 ± 1.89 | 2.0 ± 1.05 | 1.5224 | .1279 |
| SCr (µmol/L) | 77.3 ± 18.71 | 76.3 ± 18.52 | 79.9 ± 18.84 | 79.0 ± 19.22 | 0.0931 | .7606 |
| Serum UA (µmol/L) | 459.4 ± 72.76 | 452.8 ± 66.71 | 477.5 ± 88.45 | 468.6 ± 76.53 | 0.4650 | .4963 |
| eGFR (mL/min/1.73 m2) | 92.1 ± 23.05 | 92.7 ± 23.42 | 92.6 ± 23.00 | 89.4 ± 21.67 | 0.8207 | .3664 |
Abbreviations: BMI, body mass index; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; HR, heart rate; SBP, systolic blood pressure; SCr, serum creatinine; TC, total cholesterol; TG, triglycerides; UA, uric acid.
aThe distribution of TC and TG was skewed, and the Wilcoxon rank sum test was used for their inter‐group comparison; for other measures, Student's t‐test was used.
3.3.2. Efficacy evaluation of overall and allisartan‐isoproxil monotherapy
After a 4 week treatment with allisartan‐isoproxil 240 mg/day, 67.1% (326/486) of patients’ BP was controlled (BP < 140/90 mmHg), and continued monotherapy. Ultimately, the decrease in sitting SBP/DBP of these patients was 18.6 ± 11.7/10.3 ± 8.8 mmHg (all p < .0001), and the UA level decreased by 36.2 µmol/L (p < .0001) from the baseline.
3.3.3. Efficacy evaluation of combination therapies
At week 5, 160 patients with uncontrolled BP were transferred to combination therapy. In Group A + C, the decrease in sitting SBP/DBP was 19.5 ± 11.6/9.7 ± 9.2 mmHg (all p < .001) and in the UA level was 44.5 µmol/L (p = .0003). And in Group A + D, the decrease in sitting SBP/DBP was 18.1 ± 14.1/9.9 ± 10.1 mmHg (all p < .001), but the UA level was significantly increased by 27.2 µmol/L from the baseline (p = .0167). There were no significant differences between the two groups, except in the change of UA levels (intergroup p < .0001). See Table 4 and Figure 4.
TABLE 4.
Changes in BP and UA levels before and after treatment for hypertension with hyperuricemia.
| Group | Parameters | Pre‐treatment | Post‐treatment | Change (week12‐ baseline) | Statistics | p |
|---|---|---|---|---|---|---|
| Group A + C (No. = 77) | SBP (mmHg) | 154.0 ± 10.41 | 134.8 ± 13.10 | −19.5 ± 11.59 | 14.3842 | <.0001 |
| DBP (mmHg) | 96.1 ± 9.25 | 86.6 ± 10.12 | −9.7 ± 9.23 | 8.9782 | <.0001 | |
| Serum UA (µmol/L) | 477.5 ± 88.45 | 432.5 ± 94.38 | −44.5 ± 100.38 | −3.7874 | .0003 | |
| Group A + D (No. = 83) | SBP (mmHg) | 152.6 ± 11.07 | 134.7 ± 13.21 | −18.1 ± 14.05 | 11.3687 | <.0001 |
| DBP (mmHg) | 95.4 ± 8.40 | 85.8 ± 8.92 | −9.9 ± 10.08 | 8.6455 | <.0001 | |
| Serum UA (µmol/L) | 468.6 ± 76.53 | 497.7 ± 111.36 | 27.2 ± 97.36 | 2.4484 | .0167 |
The paired t‐test was used for the intra‐group comparison of the observed data before and after the treatment.
A + C, allisartan‐isoproxil tablets (240 mg) + amlodipine besylate tablets (5 mg);A + D, allisartan‐isoproxil tablets (240 mg) + indapamide sustained‐release tablets (1.5 mg); UA, uric acid.
FIGURE 4.
The levels of plasma uric acid in group A + C and group A + D at baseline and 12 week. A + D, allisartan‐isoproxil tablets (240 mg) + indapamide sustained‐release tablets (1.5 mg); A + C, allisartan‐isoproxil tablets + amlodipine besylate tablets (5 mg).
3.3.4. Logistic regression analysis on influencing factors of the recovery of hyperuricemia
The Logistic regression model of hyperuricemia recovery (serum UA < 420 µmol/L in male, or < 360 µmol/L in females) was developed with antihypertensive regimen, sex, age, BMI, history of hypertension, concomitant disease/medications, BP decrease, and eGFR as the variables. The results showed that the patients treated with A + D regimen had a lower UA recovery rate than the patients treated with A+C regimen [OR (95% CI) = 5.332 (2.320, 12.255), p < .0001], meaning that treatment with A + C regimen was more beneficial for the recovery of UA levels. See Figure 5.
FIGURE 5.
Multivariate analysis of the recovery of serum UA levels at week 12‐Logistic multivariate regression model. A + D, allisartan‐isoproxil tablets (240 mg) + indapamide sustained‐release tablets (1.5 mg); A + C, allisartan‐isoproxil tablets + amlodipine besylate tablets (5 mg). BMI, body mass index; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; SBP, systolic blood pressure.
4. DISCUSSION
In this study, we found that A+C or A+D treatments significantly improved BP levels in hypertensive patients with microalbuminuria or hyperuricemia whose BP was poorly controlled after allisartan‐isoproxil monotherapy. Meanwhile, these two regimens could both significantly reduce microalbuminuria levels in hypertensive patients with microalbuminuria. Whereas the serum UA levels were markedly decreased only in group A+C, and conversely increased in group A + D in hypertensive patients with hyperuricemia.
In aspects of microalbuminuria, the positive effects of allisartan‐isoproxil monotherapy we observed are consistent with other ARB related study findings. 21 , 22 , 23 , 24 , 25 These results indicate that renin‐angiotensin‐aldosterone system plays a key role during the occurrence and development of microalbuminuria and renal damage. Potential mechanisms involve proteinuria reduction, glomerular hemodynamics improvement, altered glomerular barrier function restoration, showing protective effects independent of the reduction in BP. 26 As for combination treatment required patients, this study showed that the UACR levels can be significantly declined by administering allisartan‐isoproxil plus either indapamide or amlodipine, with greater reduction trending in the former regimen (no statistical significance but observable trends). The similar results were observed in another study. 27
On the contrast of elevated serum levels of UA after some treatments such as hydrochlorothiazide or indapamide, 13 the improvement effects of serum UA levels of losartan and allisartan‐isoproxil have been found in some clinical studies. 28 It was confirmed in this study as well that allisartan‐isoproxil monotherapy could significantly decrease serum UA levels. A + D treatment could potentially elevate uric acid levels was mainly due to the rapid extracellular fluid volume reduction effects of indapamide, 13 partially counteracting the serum‐UA‐lowering effects of allisartan‐isoproxil. It is in line with clinical trials results of losartan, which showed elevated UA levels after losartan + hydrochlorothiazide treatment switched from ARB + CCB. 29 The related mechanism studies showed that allisartan significantly increased the expression of intestinal UA transporters ABCG2, PDZK1 and SLC2A9 in animal models, 16 and EXP3174, the active metabolite of allisartan‐isoproxil and losartan, could inhibit serum UA reabsorption protein (URAT1, OAT4) in kidney. 30 , 31 , 32 Whereas studies showed that the UA‐lowering effect of losartan was more closely related to its direct inhibition of URAT1 rather than EXP3174, suggesting different mechanisms for lowering UA between allisartan‐isoproxil and losartan.
In clinical practice, there are multiple alternative antihypertensive drug combinations, while results of this study suggest that choosing these combinations for patients with comorbidities should be more cautious. For patients with hypertension and microalbuminuria, A+C and A+D can be selected to improve BP and early renal damage. However, for patients with hyperuricemia, the effect of diuretics on elevating UA level should be taken into consideration. Under these circumstances, choosing a diuretic, if necessary, may require the combination of another drug which can reduce UA level.
The limitation of this study is mainly due to its design (a post hoc analysis). In the future, prospective controlled trials can be further designed to demonstrate the efficacy of different combination therapy on protecting target organs and improving early renal damage.
5. CONCLUSIONS
For hypertensive patients with microalbuminuria, ARB + CCB or ARB+ diuretics both are good choices basing on their improvement effect on microalbuminuria and BP. But if patients with hyperuricemia, whereas ARB+ diuretic can improve microalbuminuria, but also increases the risk of elevated serum UA.
AUTHOR CONTRIBUTIONS
Professor Ningling Sun presided over the study design, participated in the experimental process, and wrote the manuscript.
Professor Hongyi Wang participated in the experimental process and manuscript revision.
CONFLICT OF INTEREST STATEMENT
The study expenses and drugs were provided by Shenzhen Salubris Pharmaceuticals Co., Ltd. The authors did not participate in the company's drug promotions or accept any unwarranted payments.
ACKNOWLEDGMENTS
The authors thank the following institutions and investigators for their support in conducting the study: Huo Yong (Peking University First Hospital), Liu Wei (Beijing Hospital), Ding Chunhua (Aerospace Center Hospital), Zhang Lixin (Beijing Luhe Hospital Affiliated to Capital Medical University), Lv Shuzheng (Beijing Anzhen Hospital Affiliated to Capital Medical University), Dong Xichang (Dongying People's Hospital), Wang Yanfu (Affiliated Hospital of Jining Medical College), Jiang Lingyun (West China Hospital of Sichuan University), Dong Shaohong (Shenzhen People's Hospital), Gao Feng (Yanan University Affiliated Hospital), Wang Haichang (Tangdu Hospital of the Fourth Military Medical University of the People's Liberation Army), Li Xiaodong (Shengjing Hospital of China Medical University), Lin Hailong (Dalian Municipal Central Hospital), Chai Jianwen (People's Hospital of Zhengzhou), Yan Ji (Anhui Provincial Hospital), Ge Junbo (Zhongshan University), Chai Rui (Shihezi Hospital, Xinjiang Shihezi Hospital), Xu Xinjuan (First Affiliated Hospital of Xinjiang Medical University), Ning Zhongping (Shanghai Zhoupu Hospital), Zhao Mingzhong (Zhengzhou Ninth People's Hospital), Su Guohai (Central Hospital Affiliated to Shandong First Medical University), Li Lipeng (Luoyang Third People's Hospital), Liu Huiliang (Chinese People's Armed Police Force Hospital), Qiu Chaohui (Tongren Hospital, Shanghai Jiaotong University School of Medicine), Li Yuhui (Guangdong Second Provincial General Hospital), Li Rong (The First Affiliated Hospital of Guangzhou University of Chinese Medicine), Lei Da (The First Affiliated Hospital of School of Clinical Medicine of Guangdong Pharmaceutical University), Zhang Fenfang (Yangquan First People's Hospital), Guo Renwei (Shanxi Medical University Affiliated Fenyang Hospital), Wang Shouli (Characteristic Medical Center of Strategic Support Force), Wei Haisong (PKUCare Lu'an Hospital), Zhang Xingwei (The Affiliated Hospital of Hangzhou Normal University), Li Jinqiao (Central Hospital of Zibo Mining Group Co., Ltd.), Wang Jun (Zibo Central Hospital), Wei Lin (Harbin First Hospital), Zhang Guochun (the Second Hospital of Harbin), Huang Rongjie (The First Affiliated Hospital of Guangxi Medical University), Chen Yongsheng (Fifth Affiliated Hospital of Zhengzhou University), Li Gongxin (Zhujiang Hospital of Southern Medical University), Liu Jinlai (The Third Affiliated Hospital of Zhongshan University), Zhang Shuyang (Peking Union Medical College Hospital of Chinese Academy of Medical Sciences), Wang Shuqing (The First Hospital of Qiqihar), and Su Xi (Wuhan Asian Heart Hospital).
This study was registered on the Registration and Information Disclosure Platform for China Drug Clinical Studies (http://www.chinadrugtrials.org.cn/index.html) before the inclusion of the first patient. Project Registration No.: CTR20160138.
Sun N, Wang H. Effects of allisartan‐isoproxil‐based combination antihypertensive regimen in hypertensive patients with microalbuminuria or hyperuricemia. J Clin Hypertens. 2024;26:241–250. 10.1111/jch.14773
DATA AVAILABILITY STATEMENT
The data of this study is available from the corresponding author on reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data of this study is available from the corresponding author on reasonable request.